BREAKING! Californian Study Shows That SARS-CoV-2 Infections Can Be Controlled By Inhibiting Human Host SIRT5. SIRT5 Inhibitors As Potential COVID-19 Drugs

A new study by researchers from Buck Institute for Research on Aging-California, Gladstone Institute-California, University of California-San Francisco and the QBI COVID-19 Research Group (QCRG)-California has revealed that the SARS-CoV-2 coronavirus can be inhibited and controlled by downregulating human host SIRT5. The study findings showed that SIRT5 is a proviral factor and that SARS-CoV-2 levels decrease when SIRT5 is deleted or inhibited in cell-culture experiments. The study findings also show that SIRT5 inhibitors such as Suramin, Quercetin etc could possibly be used as potential COVID-19 Drugs.


 
SIRT5 also known as Sirtuin (silent mating type information regulation 2 homolog) is a protein which in humans in encoded by the SIRT5 gene. Members of the sirtuin family are characterized by a sirtuin core domain and belong to the class III of the [histone deacetylase] superfamily, and are dependent on NAD+ as co-factor of enzymatic activities. SIRT5 is one of the three sirtuins localized primarily to the mitochondrion.

Please have a heart and help to support and sustain this website and all our research and community initiatives by making a donation. You help truly means a lot and helps saves lives directly and indirectly. Thank You.
https://www.thailandmedical.news/p/sponsorship
 
SIRT5 has been found to exhibit enzymatic activities as a deacetylase, desuccinylase, and demalonylase, capable of removing acetyl, succinyl, and malonyl groups from the lysine residues of proteins. SIRT5 deacetylases and regulates carbamoyl phosphate synthetase (CPS1), the rate-limiting and initiating step of the urea cycle in liver mitochondria. Deacetylation of CPS1 stimulates its enzymatic activity.
 
SIRT5 is believed to be involved with energy metabolism, regulating the urea cycle and regulations of mitochondrial metabolism.
 
The SARS-CoV-2 non-structural protein 14 or Nsp14 is a highly conserved enzyme necessary for viral replication. Nsp14 forms a stable complex with non-structural protein Nsp10 and exhibits exoribonuclease and N7-methyltransferase activities.
 
Importantly, protein-interactome studies identified human sirtuin 5 (SIRT5) as a putative binding partner of Nsp14. SIRT5 is an NAD-dependent protein deacylase critical for cellular metabolism that removes succinyl and malonyl groups from lysine residues.
 
The study team investigated the nature of this interaction and the role of SIRT5 during SARS-CoV-2 infection.
 
The study findings showed that SIRT5 stably interacts with Nsp14, but not with Nsp10, suggesting that SIRT5 and Nsp10 are parts of separate complexes.
 
The study findings showed that SIRT5 catalytic domain is necessary for the interaction with Nsp14, but that Nsp14 does not appear to be directly deacylated by SIRT5. Furthermore, knock-out of SIRT5 or treatment with specific SIRT5 inhibitors reduced SARS-CoV-2 viral levels in cell-culture experiments. SIRT5 knock-out cells expresse d higher basal levels of innate immunity markers and mounted a stronger antiviral response.
 
The study findings indicate that SIRT5 is a proviral factor necessary for efficient viral replication, which opens novel avenues for therapeutic interventions.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2022.01.04.474979v1
 
The SARS-CoV-2 nonstructural protein 14 or Nsp14 is a component of the replication-transcription complex with two conserved domains that serve different activities.
 
These two domains are the N-terminal domain (NTD) which is an exoribonuclease (ExoN) that works from 3' to 5' and the C-terminal domain is a ribonucleic acid (RNA) cap guanine N7-methyltransferase (MTase) that works from 3' to 5'.
 
It has been found that during RNA replication, the N-terminal ExoN domain performs proofreading, thus allowing mismatched nucleotides introduced by the viral RNA polymerase to be removed. The C-terminal MTase domain of Nsp14 is an S-adenosyl methionine (SAM)-dependent methyltransferase that methylates the 5′ guanine of the Gppp-RNA cap at the N7 position, which is required for viral RNA capping.
 
Importantly, the 5′ cap is crucial for viral messenger RNA (mRNA) stability and translation, as well as for evading innate antiviral responses in the host. Nsp14 causes translational halting, participates in innate immunity evasion, activates proinflammatory signals, and orchestrates viral recombination.
 
The SARS-CoV-2 non-structural protein 14 or Nsp14 interacts with SIRT5.
 
Sirtuins are key regulators of cellular metabolism and aging that use nicotinamide adenine dinucleotide (NAD) as a co-substrate.
 
The SIRT5 binds stably with non-structural protein (Nsp14) but not with its cofactor Nsp10, and the enzymatic activity of SIRT5 is required for the association.
 
Interestingly, the knocking out or inhibiting of SIRT5 in cell culture tests has lowered viral loads, thereby indicating that SIRT5 is a proviral component required for successful viral replication.
 
It is already known that the SARS-CoV-2 virus hijacks the cellular machinery after entering the human cell, which allows for its viral proteins to physically interact with hundreds of human proteins. SIRT5 has been identified as a potential binding partner of Nsp14 in protein interactome studies. The nature of this interaction and the role of SIRT5 during SARS-CoV-2 infection were examined in this study.
 
The study findings showed that SIRT5 interacts with Nsp14 in a stable manner and that this connection is independent of Nsp10.
 
The study team interestingly discovered that the catalytic activity of SIRT5 was required for the interaction, as many SIRT5 catalytic mutants were unable to bind to Nsp14 and certain SIRT5 inhibitors prevented the association.
 
Though SIRT5 is the primary cellular desuccinylase, demalonylase, and deglutarylase, the study team were unable to find these lysine modifications on the Nsp14 protein, thus implying that SIRT5 does not modify Nsp14 directly.
 
Significantly, SIRT5 is also a proviral factor, as demonstrated by the fact that when SIRT5 is removed or inhibited in cell-culture trials, SARS-CoV-2 levels drop.
 
The study team discovered that SIRT5-knockout (KO) cells have greater basal levels of innate immunity markers and produce a stronger antiviral response, which could explain the decrease in virus levels.
 
Importantly the association between SIRT5 and Nsp14 was prevented when the SIRT5 catalytic domain was mutated or when cells were treated with a SIRT5 inhibitor. Furthermore, the strength of the contact appeared to be controlled by cellular NAD levels.
 
Utilizing mass spectrometry and immunoblotting, the researchers observed no lysine changes on Nsp14. Furthermore, SIRT5 is the only known desuccinylase, demalonylase, and deglutarylase, and these investigations were carried out in Sirt5-KD cells, which would have enriched the presence of these lysine modifications if they existed.
 
Interestingly, SIRT5-KO mice have no noticeable phenotype and have strong innate immune responses to a variety of bacterial infections. Even in mock-infected cells, the reduction in SARS-CoV-2 levels was linked with enhanced basal levels of many viral restriction factors in SIRT5-KO cells.
 
Significantly, this small but considerable increase could explain the slow propagation of SARS-CoV-2 in SIRT5-KO cells.
 
This finding also suggested that SIRT5 desuccinylation of mitochondrial antiviral signaling protein (MAVS) is not the primary mechanism causing viral levels to drop in SIRT5-KO cells.
 
The study team recommends further research into the potential link between, the Nsp14/SIRT5 interaction and the proviral role of SHIRT5 needs to be conducted.
 
Also, there are several hypotheses to consider:
 
-Firstly, Nsp14 could promote viral replication by increasing SIRT5 activity, which would decrease innate immune responses and favor viral replication.
 
-Secondly, SIRT5 could be redirected by Nsp14 to other targets, such as other viral proteins.
 
-Thirdly, as noted by the researchers, SIRT5 and Nsp10 formed distinct complexes and SIRT5 boosted Nsp14 MTase activity marginally. The absence of SIRT5 causes a deficiency in cap methylation, more efficient immunological detection of viral RNA, and greater immune response.
 
Collectively, taken together, SIRT5 is a possible pharmacological target that could help fight viral infections in general and SARS-CoV-2 in particular. Inhibiting SIRT5 will certainly never be utilized as the first line of defense; however, it could be used along with medications that directly target viral enzymes to create innovative COVID-19 treatment regimens.
 
Examples of SIRT5 inhibitors include Suramin and also Quercetin.
https://pubmed.ncbi.nlm.nih.gov/17355872/
 
https://www.sciencedirect.com/science/article/pii/S0753332218374146
 
Read Also: https://www.thailandmedical.news/news/quercetin-emerging-as-one-of-the-must-take-covid-19-supplements-especially-when-considering-the-omicron-variant-and-long-covid-19-issues
 
Please have a heart and help to support and sustain this website and all our research and community initiatives by making a donation. You help truly means a lot and helps saves lives directly and indirectly. Thank You.
https://www.thailandmedical.news/p/sponsorship
 
For the latest on COVID-19 Drugs keep on logging to Thailand Medical News.